Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy.

Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1alpha and PPARgamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1alpha activates glycolytic genes and PPARgamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1alpha in mice prevents hypertrophy-induced PPARgamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass.

Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. A single university hospital. One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

Imagerie cardiaque non invasive: apport spécifique en clinique des nouvelles modalités (II). Evaluation fonctionnelle [Cardiac imaging: specific clinical role of newly developed non invasive techniques. Part II: functional evaluation].

The non-invasive evaluation of myocardial ischemia is a priority in cardiology. The preferred initial non-invasive test is exercise ECG, because of its high accessibility and its low cost. Stress radionuclide myocardial perfusion imaging or stress echocardiography are now routinely performed, and new non-invasive techniques such as perfusion-MRI, dobutamine stress-MRI or 82rubidium perfusion PET have recently gained acceptance in clinical practice. In the same time, an increasing attention has been accorded to the concept of myocardial viability in the decisional processes in case of ischemic heart failure. In this indication, MRI with late enhancement after intravenous injection of gadolinium and 18F-FDG PET showed an excellent diagnostic accuracy. This article will present these new imaging modalities and their accepted indications.

Cardiac paraganglioma: diagnostic work up and review of the literature.

Paraganglioma of the heart are potentially invasive, highly vascularized tumors for which complete resection may be curative. Derived from the cardiac wall in most instances, resectability can be assessed after integration of the data provided by MRI in T2 sequence, and coronarography. A fully documented case of a large cardiac pheochromocytoma of the left atrium and AV groove is reported and the pertinent literature on the subject is here presented.

Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2.

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

Electroencephalography (EEG) for neurological prognostication after cardiac arrest and targeted temperature management; rationale and study design.

BACKGROUND: Electroencephalography (EEG) is widely used to assess neurological prognosis in patients who are comatose after cardiac arrest, but its value is limited by varying definitions of pathological patterns and by inter-rater variability. The American Clinical Neurophysiology Society (ACNS) has recently proposed a standardized EEG-terminology for critical care to address these limitations. METHODS/DESIGN: In the TTM-trial, 399 post cardiac arrest patients who remained comatose after rewarming underwent a routine EEG. The presence of clinical seizures, use of sedatives and antiepileptic drugs during the EEG-registration were prospectively documented. DISCUSSION: A well-defined terminology for interpreting post cardiac arrest EEGs is critical for the use of EEG as a prognostic tool. TRIAL REGISTRATION: The TTM-trial is registered at ClinicalTrials.gov (NCT01020916).

Too cold may not be so cool: spontaneous hypothermia as a marker of poor outcome after cardiac arrest.

In a recent issue of Critical Care, den Hartog and colleagues show an association between spontaneous hypothermia, defined by an admission body temperature < 35°C, and poor outcome in patients with coma after cardiac arrest (CA) treated with therapeutic hypothermia (TH). Given that TH alters neurological prognostication, studies aiming to identify early markers of injury severity and outcome are welcome, since they may contribute overall to optimize the management of comatose CA patients. This study provides an important message to clinicians involved in post-resuscitation care and raises important questions that need to be taken into account in future studies.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine.

OBJECTIVES: To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS: GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS: Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ≥72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron-specific enolase at 48-72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.

Combined functional and viability cardiac MR imaging in a single breathhold

The combination of cardiac viability and functional information enhances the identification of different heart tissues in the setting of ischemic heart disease. A method has recently been proposed for obtaining black-blood delayed-enhancement (DE) viability images using the stimulated-echo acquisition mode (STEAM) MRI pulse sequence in a single short breathhold. The method was validated against conventional inversion-recovery (IR) DE images for identifying regions of myocardial infarction (MI). The method was based on the acquisition of three consecutive images of the same anatomical slice. One image has T(1)-weighted contrast in which infarction appears bright. The two other images are used to construct an anatomical image of the heart, which is combined with the first image to produce a black-blood viability image. However, using appropriate modulation and demodulation frequencies, the latter two images bear useful information about myocardial deformation that results in a cardiac strain-encoding (SENC) functional image. In this work, a method is proposed for obtaining three consecutive SENC images in a single acquisition that can be combined to produce a composite image of the heart, which shows both functional and viability information. The proposed technique reduces scan time by one-half, compared with separate acquisitions of functional and viability images, and alleviates misregistration problems caused by separate breathholds.

Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.

PURPOSE: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. PATIENTS AND METHODS: Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. RESULTS: 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). CONCLUSION: Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.

On some numerical aspects of an active strain model in cardiac mechanics

We are interested in the development, implementation and testing of an orthotropic model for cardiac contraction based on an active strain decomposition. Our model addresses the coupling of a transversely isotropic mechanical description at the cell level, with an orthotropic constitutive law for incompressible tissue at the macroscopic level. The main differences with the active stress model are addressed in detail, and a finite element discretization using Taylor-Hood and MINI elements is proposed and illustrated with numerical examples.

Perforation cardiaque d'un ulcère gastrique: une cause inhabituelle de décès, après résection oesogastrique pour carcinome épidermoïde de l'oesophage [Cardiac perforation by a gastric ulcer: an unusual cause of death, after an esophageal and gastric resection of an epidermoid esophageal carcinoma]

We report here the case of a 55 year old female that underwent surgery for a well differentiated squamous cell carcinoma of the esophagus (middle third). Four months after surgery, she complains of neck pain, for which she is prescribed non steroidal antiinflammatory drugs (NSAID). A CT-scan and a Barium swallow are then normal. After three weeks of treatment, the patient is admitted on emergency to the Intensive Care Unit for a resuscitation hematemesis and atrial fibrillation with a fast ventricular response. The symptoms are stabilized after the transfusion of a few packed red blood cells. A few hours later, however, a massive hematemesis recurs and the patient dies despite intense resuscitation measures. Autopsy reveals three gastric ulcers, one of which had perforated through the cardiac left ventricular wall